Vascular head pain including migraine and cluster headaches, are poorly understood but remain a major cause of morbidity and economic loss today. We have developed an experimental in vivo model to study the trigeminovascular system in rat and guinea pig which may be relevant to migraine pathophysiology. We have identified and quantitated plasma extravasation, and visualized endothelial vesicle and vacuole formation, platelet aggregation, mast cell secretion and degranulation within dura mater following trigeminal ganglion stimulation. We observed that 5-HT1 agonists useful in the treatment of vascular headaches, significantly reduce the platelet, mast cell, endothelial and plasma extravasation selectively within dura mater. Other preliminary data suggest that the 5- HT1 receptors are prejunctional, are coupled to inhibition of neuropeptide release, and are probably 5-HT1B in rat the 5-HT1D-like in guinea pig. Experiments are proposed which will develop and characterize the inflammatory response using ultrastructural examination of the dura mater in rat and guinea pig including the possible expression of endothelial surface antigens such as endothelial leukocyte adhesion molecule 1 (ELAM- 1), VCAM-1 (vascular cell wall adhesion molecule 1), ICAM and platelet activation dependent granule-external membrane protein (PADGEM) after neurogenic stimulation. Structure-activity relationships and the relevant receptor subtypes will be determined by the administration of neuropeptide analogues and NK receptor blockers. Pharmacological studies using selective and specific agonists at the 5-HT1 receptor subtypes will characterize the relevant 5-HT receptor subtype in the guinea pig which mediates inhibition of release and blockade of inflammation, and explore the possibility that blockade of inflammation may be mediated by other prejunctional receptors. In situ hybridization and Northern blots will determine whether the 5-HT1D receptor mRNA is expressed within populations of trigeminal neurons that project to intracerebral vascular targets, and within human trigeminal ganglia. By so doing, a rationale basis for the pathophysiology and pharmacotherapy of vascular headaches may follow.